Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, a friend and colleague, Dr. Tia Higano, who is a GU Medical Oncologist, who needs no further introduction, out in Seattle in the US as well. Thank you so much for being here with us today, Dr. Higano.

Celestia Higano: Thank you for asking me to.

Alicia Morgans: Wonderful. Tia, you've done a number of studies looking at real-world data sets, and I just wanted to talk with you about one of the more recent studies that you recently published, looking at patients who have metastatic CRPC and looking at the lines of therapy that they've received to understand how the type of number of lines of therapy actually are being delivered in the real world, and how those lines of therapy may impact prostate cancer-specific in overall type survival, and you did this in the Flatiron database. Thank you so much for coming to speak with us about that today.

Celestia Higano: You're welcome. I think the thing that prompted us to look at this was, one, the approval of radium 223, and we wanted to understand how radium fit into this. But this is a great opportunity to look at a large number of patients, I think it's over 2,500 patients, in this so-called Flatiron database. Now, and we're talking today in 2021, I think it's important to understand that this data was collected between 2013 and 2017, so would preface that, compared to today, by saying that this is pre-PARP, pre doing a lot of genetic testing, et cetera, that should be taken into account as we go along in our discussion.

But as you said, some of the findings of this study were really unexpected, and the Flatiron database is, is a very powerful database, compared to looking at other possible data sets like in SEER-Medicare database, because the patients collected in the Flatiron database, first, as of the last count and I don't know, it's probably higher than that, they have over 2 million cancer patients across the country in very diverse, so geographic settings, in both community oncology practices, as well as some academic sites, I think there's 800 total sites and I don't know how many practices, but anyway, a lot of sites.

One of the downsides for looking at prostate cancer is that the Flatiron database doesn't contain urology practices, and we know our urology colleagues are treating a lot of these patients, so we have to take that into account. But this data from the Flatiron database is, first of all, when you use a Flatiron database, you, of course, need to tell them exactly what data you're looking for, and then they'll go get it. And this data is highly curated, unlike the SEER-Medicare data, where we sort of get what we have. They actually manually abstract the data that's requested and needed for whatever study you're doing, and it's not abstracted by high school students, it's abstracted by oncology nurses or tumor registrars, people who sort of know the field, and these are overseen by medical oncologists, so it's quite high quality data. So, when you look at this data, I think it gives you the true, real-world, what's happening out there, picture of this population of patients.

And as you alluded to, we found that 77% of all metastatic CRPC patients get some treatment with a life-prolonging therapy, but that also means that the difference, 23%, don't get any life-prolonging therapy, which is kind of disturbing in this day and age. Now, you said, and it's possible, that in the earlier part of the timeframe we studied, 2013 and 2017, maybe there were issues with insurance approval or availability, et cetera, et cetera. But as time went on, it would be hard to explain that as the reason for those patients not getting treated.

Alicia Morgans: Yeah, that is a surprisingly high number from my view. There are patients who have advanced dementia or who have very advanced co-morbidities, are completely asymptomatic from their mCRPC, and in those settings, sometimes we will not use intensification strategies or further lines of therapy. But it feels, at least in my practice, like those are relatively rare cases, and 23% is almost a quarter of all patients with mCRPC who are not getting the therapy.

Celestia Higano: Yeah. The other interesting finding is what happened after that. So, of the people who did get a first-line life-prolonging therapy, only about half of those, so 50% of the 77%, got a second-line therapy, and then half, again, of those got a third-line therapy after second-line. So I don't honestly understand that, because it seems like we can often get a lot more therapy into our patient than that. In the paper, I would say, we did not speculate on why we had that finding. That might be an interesting thing to find out, maybe from physician focus groups or whatever, but I think that there's a significant proportion of patients with metastatic CRPC out there who seem to be undertreated.

Alicia Morgans: I would agree, at least in this data set. But this isn't outlandish data either. This, I think, has been corroborated in other settings.

Celestia Higano: Yeah. Yes. And I think the big ticket take home message from this data is, if you just look at the median overall survival of the different populations, those who did receive at least one first-line, I guess you'd say, life-prolonging therapy compared to those who got none, the median survival was in the 23+ month range for those who got something, versus 10 months for those who got nothing. And that's a huge difference.

Now, the other thing that we saw, was we looked at the use of so-called bone health agents, either zoledronic acid or denosumab, and that was also lower than not, although subsequently, it's been shown that actually a lot of people are not following the guidelines on that, so 60% of patients were treated with bone health agents in this Flatiron database. And one of my thoughts about this is, now that we've shown these things, not only in this study, but in the other real-world studies, are institutions taking this information to try to do something about this? I don't know, but I think that's what they really should be doing with this data. We have all these treatment pathways and all this, but who's minding the store. That's kind of my thought about it.

Alicia Morgans: It's interesting. I think that we all feel like we're doing all of these things, especially things like supportive care and for bone health, but even in my own clinic, sometimes we'll have fellows in clinic and they'll come back and they'll say, "Well, you wrote that you were going to be getting this DEXA scan for this patient with hormone-sensitive disease who's on long-term ADT who needs bone health consideration for fragility fracture prevention," or, "this patient transitioned to mCRPC a couple of months ago, are you going to start a bone health agent?" And maybe I wrote, pending dental evaluation or something and I just didn't follow up back at the dentist. So this happens in, in all of our practices, and it's something I think we all strive to take care of. But like you said, we have to have some mechanisms to help us, because we're just human beings and we're certainly dealing with multiple things during every visit, including making sure that the disease is controlled and not progressing.

So, it's interesting, some groups that I find most successful at this, there are some urology practices that have integrated APPs into clearly dedicating themselves to these survivorship type issues, and even thinking about things like blood pressure, which I try to monitor as well, particularly with some of these agents that can elevate blood pressure or hemoglobin A1C monitoring and things. So there are strategies that can do this, but we need data like yours, like this paper, to reflect back what we're doing as a whole. And then I think practices need to do these kinds of quality improvement checks on their own work, to develop these strategies to support them in implementing these kinds of survivorship care strategies and other strategies to really systematize this process, because it's tough to rely just on our own memory, sometimes.

Celestia Higano: Absolutely. And you know what? I love working with APPs in my practice, but I do think that EMRs that have these flags for us is probably going to be the way it goes over time.

Alicia Morgans: Absolutely.

Celestia Higano: Because that would be very easy for us to be alerted, that, "Oops, we dropped the ball here. We need to add it. We need to pick it up and throw it."

Alicia Morgans: Yes, we need something better than just a fellow saying, "Hey, Dr. Morgans, you missed this." Yes. Agreed. And actually I practiced a number of years ago in a VA system, it was a very long time ago actually, when I was a resident, and there were flags for a lot of different things that were always so helpful. So I completely agree and hope we can use studies like yours to really help us and encourage our teams and our institutions, maybe, to try to use some of these flags.

One of the other things that I noticed in your study that was really interesting was that there was also a fair amount of AR-targeted agent use, and then subsequent AR-targeted agent. And certainly, maybe that's better than not using anything at all and completely having patients drop off of further lines of therapy, but we don't expect that many patients are going to respond to that second AR-targeted agent, and it was actually a fair number of patients within your study. What are your thoughts on that?

Celestia Higano: Yeah, no, that was surprising, because really, Abi followed by Enza or Enza followed by Abi, we have reasons for doing the order of these days, but in those days, there was no reason for doing it. And that was really the most common second and third-line therapy, was one after the other, which, even at that time, was not really consistent with NCCN guidelines. And I think, number one, during the interval when the study was done, I don't think we really had that appreciation as much as we have today, about how it's not totally useless, but it's not commonly very effective to add one to the other or one after the other.

But, even today, I'm afraid, there's still a lot of that. And I think it's partly just because, hey, these are oral agents. Now they're not so hard to get. I mean, again, which is interesting, because in the UK, you can't do that because you're only allowed one or the other, but you can't give one and then the other, which maybe we should think about here.

Alicia Morgans: Yeah, yeah. No, it's interesting. Well, as I consider this study, and again, congratulations to you and your team for getting this work done and really holding up the mirror to us as we practice, as we try to improve what we're doing and help patients have better outcomes, this is a fantastic way to help us do that. What would your final thoughts be? What is your message to viewers who are thinking about this work?

Celestia Higano: Well, I think, hopefully the take-home message that the Abi-Enza combination follow on was okay, but it's really not the best thing to do for patients now, just because of the high number of patients who don't respond very well. Although we do know that some patients will get benefit from it, but as a general rule, it should not be the most common second and third-line therapy that we give to our patients.

The other thing is, again, we talked about this at the beginning, how can we let any patient with metastatic castration-resistant prostate cancer, for the most part, die without having any life-prolonging therapy, given the huge difference in median overall survival between those who did and those who didn't. And then maybe last, not to get into too much detail, but really try to remember the utility in the bone health agents, and especially now that we have data from the ERA 223 trial, where the patients who got radium that did not have bone health agents had more problems with fractures. we've learned a lot since this cohort of patients in this study, but we need to think of that even more now. It's even more important. So I think those would be the main things I would stay are the take-home messages.

Alicia Morgans: Yeah. Well, this was a real-world study with some very, very important real-world implications, so I sincerely appreciate you walking us through it and helping us to understand that we're not always doing as well as we believe we're doing. And that's okay. That is what it is. But it takes these kinds of studies to help us, again, hold up that mirror, think about how we're taking care of our patients, and then start to implement strategies that can help us give better care or deliver better care to our patients. And really, at the end of the day, we can do better. We can improve outcomes if we even get one line of additional therapy into these patients with mCRPC. So, thank you so much for the work that you do and for taking the time to speak with me about it today.

Celestia Higano: It was a pleasure, Alicia. Thank you very much.